WEIGHT LOSS-INDUCED MODIFICATION OF THE GENOMIC NETWORK UNDERLYING OBESE ASTHMA. The primary scientific objective of this project is to understand the molecular mechanisms by which weight loss improves asthma symptoms. Obesity and asthma are two of the most common chronic medical conditions in the world and are each major heritable causes of morbidity. Obesity is both a significant asthma susceptibility risk factor and a major modifier of asthma control and severity. Importantly, it is modifiable risk factor: obese asthmatics who undergo major weight reductions (5-50%) through dieting, exercise, and/or bariatric surgery often have substantial improvements in respiratory symptoms and asthma control. These clinical and epidemiological relationships between asthma and obesity are well established; what are not are their underlying molecular mechanisms. Elucidating the genomic modifications induced by weight loss that lead to improvements in asthma control would be of great scientific and public health importance. I propose to use genomic epidemiological and network approaches to identify modifiable genes and pathways underlying the obesity-asthma relationship. Given that gene expression profiling of blood and adipose tissues has previously identified clustered sets of biologically plausible genes separately related to asthma and obesity phenotypes (e.g., inflammatory and immune processes), I hypothesize that within the human transcriptome (i) there exist one or more local gene co-expression modules specific to obese asthma; and (ii) that weight loss in asthmatics results in improvements in asthma control coincident with induction of specific alterations in the expression of critical co-expression module members. I will first use previously published data to define preliminary gene co-expression modules of obese asthma to then be tested in a novel cohort specifically developed to longitudinally assess the molecular relationships underlying the asthma-obesity overlap. It will be a prospective cohort of obese individuals (n = 100, ~50% with asthma) undergoing laparoscopic sleeve gastrectomy (LSG) with disease-relevant gene expression and asthma/obesity phenotype data measured both prior to the surgery and post-operatively at three months. Smaller unpublished genomic datasets related to weight loss interventions shared by collaborators will further replicate gene networks associated with changes in obese asthma in the LSG cohort.